Certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines; dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula:                    
     or pharmaceutically acceptable addition salts thereof, wherein: 
     X, Y and Z are the same or different and represent optionally substituted carbon or nitrogen; 
     R 1  and R 2  independently represent organic or inorganic substituents; 
     R 3  and R 4  are variables independently representing inorganic or organic substituents; 
     A represents C 1 -C 4  alkylene; and 
     R 5 , R 6 , and R 7  independently represent hydrogen or C 1 -C 6  alkyl, 
     which compounds bind selectively with high affinity to the dopamine D 4  receptor subtype and are therefore of use in treatment of various neuropsychological disorders.

This is a divisional of application Ser. No. 09/177,956 filed Oct. 23,1998 now U.S. Pat. No. 6,040,448, which claims priority from U.S.Provisional Application Ser. No. 60/063,149, filed Oct. 24, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain 1-(2-naphthyl) and1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines and pharmaceuticalcompositions containing such compounds. It also relates to the use ofsuch compounds in the treatment or prevention of psychotic disorderssuch as schizophrenia and other central nervous system diseases.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₄ receptor subtype has recently beenidentified (Nature, 347: 146 (Sokoloff et al., 1990)). Its uniquelocalization in limbic brain areas and its differential recognition ofvarious antipsychotics suggest that the D₄ receptor may play a majorrole in the etiology of schizophrenia. Selective D₄ antagonists areconsidered effective antipsychotics free from the neurological sideeffects displayed by conventional neuroleptics.

Various 4-benzylpiperazines have been described. See, for example, Arch.Med. Res., 25: 435-440 (Terron et al., 1994) and Toxicol. Appl.Pharmacol., 7: 257-267 (Schmidt and Martin, 1965).

SUMMARY OF THE INVENTION

This invention provides novel compounds which interact with dopaminesubtypes. Accordingly, in a broad aspect, the invention providescompounds of Formula I:

or pharmaceutically acceptable addition salts thereof, wherein:

X, Y and Z are the same or different and represent CR_(c) or nitrogen;

R_(c) represents hydrogen, halogen or C₁-C₆alkyl;

R₁ and R₂ independently represent hydrogen, halogen, hydroxy,

C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂NH₂, provided that,when Y and Z represent CH, and R₃ and R₄ are both hydrogen, R₁ and R₂are not hydrogen simultaneously; or

R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group or a C₁-C₃alkylene oxy group;

R₃ and R₄ are the same or different and represent hydrogen, halogen,C₁-C₆ alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkylamino where each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl;

A represents C₁-C₄ alkylene; and

R₅, R₆, and R₇ independently represent hydrogen or C₁-C₆ alkyl.

Dopamine D₄ receptors are concentrated in the limbic system (Science,265: 1034 (Taubes, 1994)) which controls cognition and emotion.Therefore, compounds that interact with these receptors are useful inthe treatment of cognitive disorders. Such disorders include cognitivedeficits which are a significant component of the negative symptoms(social withdrawal and unresponsiveness) of schizophrenia. Otherdisorders include those involving memory impairment or attention deficitdisorders.

Compounds of the present invention demonstrate high affinity andselectivity in binding to the D₄ receptor subtype. These compounds aretherefore useful in treatment of a variety of neurospychologicaldisorders, such as, for example, schizophrenia, psychotic depression andmania. Other dopamine-mediated diseases such as Parkinsonism and tardivedyskinesias can also be treated directly or indirectly by modulation ofD₄ receptors.

Thus, in another aspect, the invention provides methods for treatmentand/or prevention of neuropsychochological or affective disordersincluding, for example, schizophrenia, mania, dementia, depression,anxiety, compulsive behavior, substance abuse, memory impairment,cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonismand dystonia, and motion disorders related to the use of neurolepticagents. In addition, the compounds of the invention are useful intreatment of depression, memory-impairment or Alzheimer's disease bymodulation of D₄ receptors which selectively exist in limbic area knownto control emotion and cognitive functions. Further, the compounds ofthe present invention are useful for the treatment of other disordersthat respond to dopaminergic blockade, e.g., substance abuse andobsessive compulsive disorder. These compounds are also useful intreating the extrapyramidal side effects associated with the use ofconventional neuroleptic agents.

In yet another aspect, the invention provides pharmaceuticalcompositions comprising compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the invention encompasses substituted 1-(2-naphthyl)and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines of Formula I.Preferred compounds of Formula I are those where at least one of R₁ andR₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or where R₁ andR₂ together represent 3,4-methylenedioxy. Still other preferredcompounds of Formula I are those where

represents 4-alkylquinolinyl, 4,6-dialkylquinolinyl,4,7-dialkylquinolinyl, 4,8-dialkylquinolinyl, 4-haloquinolinyl, or4-alkyl-6-alkoxyquinolinyl. Preferably, only Z is R_(c). More preferredcompounds of Formula I are those where at least one of R₁ and R₂ ischloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl,trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. Particularly preferred compounds of Formula I arethose where R₂ is hydrogen and R₁ is methyl or chloro. In addition,preferred compounds of Formula I are those where A is methylene orethylene, and R₅ is hydrogen.

Particularly preferred compounds of Formula I are those where

represents quinolin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl,quinoxalin-2-yl, or naphth-2-yl.

The invention also encompasses compounds of formula II:

wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R_(c), and R₇ carry the same definitions as setforth above for Formula I.

Preferred compounds of Formula II are those where at least one of R₁ andR₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or where R, andR₂ together represent 3,4-methylenedioxy. Still other preferredcompounds of Formula II are those where the both R₃ and R₄ are hydrogen,or the R_(c), R₃ and R₄ substitution on the quinoline ring provides a4-alkylquinolinyl, 4,6-dialkylquinolinyl, 4,7-dialkylquinolinyl,4,8-dialkylquinolinyl, 4-haloquinolinyl, or 4-alkyl-6-alkoxyquinolinylcompound. More preferred compounds of Formula II are those where A ismethylene and at least one of R₁ and R₂ is chloro, fluoro, methyl,ethyl, butyl, isopropyl, n-propyl, trifluoromethyl, trifluoromethoxy, orwhere R₁ and R₂ together represent 3,4-methylenedioxy. Particularlypreferred compounds of Formula II are those where R₃ and R₄ arehydrogen, A is methylene, R₂ is hydrogen and R₁ is methyl or chloro.

Particularly preferred compounds of Formula II are quinolin-2-ylderivatives where R₃ and R₄ are hydrogen. Other particularly preferredcompounds of Formula II are 5,6,7,8-tetrahydroquinolin-2-yl derivativeswhere R₃ and R₄ are hydrogen.

Also encompassed within the invention are compounds of Formula III:

wherein:

R₁, R₂, R₃₁ R₄, R₅, R₆, and R₇ carry the same definitions as set forthabove for Formula I.

Preferred compounds of Formula III are those where at least one of R₁and R₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or where R₁and R₂ together represent 3,4-methylenedioxy. More preferred compoundsof Formula III are those where A is methylene and at least one of R₁ andR₂ is chloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl,trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. Particularly preferred compounds of Formula III arethose where R₃ and R₄ are hydrogen, A is methylene, R₂ is hydrogen andR₁ is methyl or chloro.

Particularly preferred compounds of Formula III are quinoxalin-2-ylderivatives where R₃ and R₄ are hydrogen.

The invention further provides compounds of formula IV:

wherein:

R₁, R₂, R₃, R₄, R₅, R₆, and R₇ carry the same definitions as set forthabove for Formula I.

Preferred compounds of Formula IV are those where at least one of R₁ andR₂ is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or where R₁ andR₂ together represent 3,4-methylenedioxy. More preferred compounds ofFormula IV are those where A is methylene and at least one of R₁ and R₂is chloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl,trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. Particularly preferred compounds of Formula IV arethose where R₃ and R₄ are hydrogen, A is methylene, R₂ is hydrogen andR₁ is methyl or chloro.

The invention also encompasses compounds of formula V:

wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R_(c), and R₇ carry the same definitions as setforth above for Formula I.

Preferred compounds of Formula V are those where R_(c) is hydrogen; andat least one of R₁ and R₂ is halogen, alkyl, trifluoromethyl,trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. More preferred compounds of Formula V are thosewhere R_(c) is hydrogen, A is methylene and at least one of R₁ and R₂ ischloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl,trifluoromethyl, trifluoromethoxy, or where R₁ and R₂ together represent3,4-methylenedioxy. Particularly preferred compounds of Formula V arethose where R₃ and R₄ are hydrogen, A is methylene, R₂ is hydrogen andR₁ is methyl or chloro.

The particularly preferred compounds of Formula V are naphth-2-ylderivatives where R₃ and R₄ are hydrogen.

Particularly preferred compounds of Formulae I-V are those where R₅, R₆,and R₇ are hydrogen.

The invention further provides intermediates useful in the preparationof compounds of Formula I. Such intermediates include those of FormulaVIII.

where X, Y, Z, R₃, R₄, and R₆ and R₇ are as defined above for Formula I.

In certain situations, the compounds of this invention I may contain oneor more asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)n—ACOOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By the use herein of dashed lines in the structural representations ofthe compounds of the invention is meant that the carbon atoms connectedby the dashed line are linked either by single or double carbon-carbonbonds.

The use herein of the following structure

where A represents C₁-C₄ alkylene and R₅ is hydrogen or lower alkyl(“the AR₅ group”), means alkylene groups having from 1-4 carbon atomseach of which carbon atoms is optionally substituted with a lower alkylgroup. Examples of such a structure are methylene, ethylene, propylene,and butylene. A particularly preferred AR₅ group according to theinvention is methylene, i.e., —CH₂—.

By alkyl or lower alkyl in the present invention is meant C₁-C₆ alkyl,i.e., straight or branched chain alkyl groups having 1-6 carbon atoms,such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl.

By alkoxy or lower alkoxy in the present invention is meant C₁-C₆alkoxy, i.e.,straight or branched chain alkoxy groups having 1-6 carbonatoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By cycloalkoxy in the present invention is meant cycloalkylalkoxy groupshaving 3-7 carbon atoms where cycloalkyl is defined above.

By C₁-C₂ alkylene dioxy group is meant a group of the formula:

By C₁-C₃ alkylene oxy group is meant a group of the formula:

By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

Representative compounds of the invention are shown below in Table 1.

TABLE 1

The compounds of the invention are useful in the treatment ofneuropsychological disorders; the pharmaceutical utility of compounds ofthis invention is indicated by the assays for dopamine receptor subtypeaffinity described below in the Examples. The interaction of the1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)-piperazines ofthe invention with dopamine receptor subtypes results in thepharmacological activities of these compounds.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Representative illustrations of methods suitable for the preparation ofcompounds of the present invention are shown in the following Schemes.Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention. For example, in certainsituations, protection of reactive moieties such as amino groups, willbe required.

An azanaphthyl compound of Formula I may be prepared according to Scheme1.

In Scheme 1, R₁, R₂, R₃, R₄, R₅, R₆, R₇, X, Y and Z are as defined abovefor Formula I.

As shown, an azanaphthyl compound of general structure VI, having anappropriate leaving group L at the position indicated, is condensed witha piperazine compound of general structure VII to provide a1-azanaphthyl piperazine of general structure VIII. Compound VIII maythen be condensed with a benzylic compound of general structure IXhaving an appropriate benzylic leaving group L₂ to provide a1-azanaphthyl-4-(1-phenylmethyl)piperazine of Formula I. The leavinggroups L and L₂ may be halides, sulfonate esters or the like. Thosehaving skill in the art will recognize that the starting materials maybe varied and additional steps employed to produce compounds encompassedby the present invention.

Alternatively, an azanaphthyl compound of the invention may be preparedaccording to Scheme 2.

In Scheme 2, R₁, R₂, R₃, R₄, R₅, R₆, R₇, X, Y and Z are as defined abovefor Formula I.

As shown, an azanaphthyl compound of general structure X, having anappropriate leaving group L at the position indicated, is condensed witha 1-substituted piperazine compound of general structure XI to provide a1-azanaphthyl-4-(1-phenylmethyl)piperazine of Formula I. The leavinggroup L may be a halide, sulfonate ester or the like. Those having skillin the art will recognize that the starting materials may be varied andadditional steps employed to produce compounds encompassed by thepresent invention.

Naphthyl compounds of the invention may be prepared according to Scheme3.

In Scheme 3, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ carry the same definitions asset forth above for Formula I.

As shown, an 2-naphthylpiperazine compound of general structure XII iscondensed with a benzylic compound of general structure IX having anappropriate benzylic leaving group L₂ to provide a1-naphthyl-4-(1-phenylmethyl)piperazine of Formula I. The leaving groupL₂ may be a halide, a sulfonate ester or the like. The startingmaterials are either commercially available or may be prepared usingcommon synthetic methods described within the body of chemicalliterature.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present inventions, as demonstrated by the followingexamples. In some cases, protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral, the need for such protecting groups will be apparent to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE 1

1. 2.4-Dichloroquinazoline

A solution of 25 g of benzoyleneurea and 12 mL of diethyl aniline in 200mL of phosphorus oxychloride is refluxed for 4 days after which excessphosphorus oxychloride is removed on a rotovap and the remaining residuepoured onto ice. The mixture is then extracted with ethyl acetate andthe combined organic extracts washed with water, 1 N NaOH solution,dried and concentrated. The residue is recrystalized from isopropanol toprovide 11 g of the dichloroquinazoline as off-white needles (m.p.64-66° C.).

2. 2-Chloroquinazoline

A two-phase mixture of a solution of 2, 4-dichloro-quinazoline (5 g) inmethylene chloride (100 mL) covered with 100 mL of saturated brinecontaining 9% NH₄OH is treated with powdered zinc (5 g) and theresultant mixture is then refluxed for 4 h, cooled and filtered throughcelite. The organic layer is removed, diluted with ethyl acetate (100ml), washed with 1 N HCl solution, dried and concentrated.

3. 2-Piperazinylquinazoline

A solution of 2-chloroquinazoline (5 g) in 20 mL of toluene is addeddropwise to a refluxing solution of piperazine (20 g) in 150 mL oftoluene and the resultant solution refluxed for an additional 24 h.After cooling to 0° C. for 0.5 h, the solution is filtered and thefiltrate extracted with 10% acetic acid The aqueous extracts are washedwith ether, basified and extracted with toluene. The toluene layer isthen washed with water, dried and concentrated. Finally, the material isplaced under vacuum overnight (6.8, m.p. 188-121° C.).

4. 2-(4-((4-chlorophenyl)methyl)piperazinyl)quinazoline

A solution of 1-quinazolin-2-ylpiperazine (250 mg, 1.2 mmol) and4-chlorobenzyl bromide (220 mg) in acetonitrile (10 mL) containingpotassium carbonate (500 mg) is stirred and heated at 60° C. for 4 h.After cooling the reaction is partitioned between ether and water andthe organic layer extracted with 1 N HCl. The acidic extract is thenbasified, extracted with chloroform and the organic layer is dried andconcentrated to provide the product, which may alternatively be named1-(quinazolin-2-yl)-4-(1-[4-chlorophenyl]methyl) piperazinehydrochloride, as a colorless oil (310 mg, 87%). The oxalate salt isprepared in isopropanol. ¹H NMR (DMSO) 9.2 (s, 1H), 7.82 (d, J=4 Hz,1H), 7.72 (T, 1H), 7.25-7.5 (m, 6H), 3.9 (m, 4H), 3.75 (s, 2H), 2.75 (m,4H).

EXAMPLE 2

1. 2- Piperazinylquinoxaline

2-Hydroxyquinoxaline (1.5 g) is heated in phosphorus oxychloride (10 mL)for 12 h, after which the reaction is concentrated and the residuepartitioned between methylene chloride and 1 N NaOH. The resulting crudechloride is taken up in toluene (10 mL) and this solution is then addeddropwise to a refluxing solution of piperazine (5 g) in toluene (40 mL).The resulting solution is refluxed for an additional 24 h, cooled to 0°C. for 0.5 h, filtered and concentrated. The filtrate is extracted with10% acetic acid and the aqueous extracts washed with ether, basified andextracted with toluene. The toluene layer is washed with water, driedand concentrated. The concentrated material, which may alternatively benamed quinoxalin-2-ylpiperazine, is placed under vacuum overnight (1.2g, 77%, m.p. 74-76° C.). ¹H NMR (CDCl₃) 8.6 (s, 1H), 7.87 (dd, J=8, 1Hz, 1H), 7.68 (dd, J=8, 1 Hz, 1H), 7.57 (ddd, J=8, 7, 1 Hz, 1H), 7.39(ddd, J=8, 7, 1 Hz, 1H), 3.76 (t, J=5 Hz, 4H), 3.02 (t, J=5 Hz, 4H).

2. 1-(Quinoxalin-2-yl)-4-(1-[4-methylphenyllmethyl]piperazine oxalate

A solution of quinoxalin-2-ylpiperazine (325 mg, 1.53 mmol) and4-methylbenzyl bromide (340 mg) in acetonitrile (10 mL) containingpotassium carbonate (500 mg) is stirred and heated at 60° C. for 4 h.After cooling, the reaction is partitioned between ether and water andthe organic layer extracted with 1 N HCl. The acidic extract is thenbasified and extracted with chloroform. The organic layer is dried andconcentrated to provide the product as a colorless oil (320 mg, 66%).The oxalate salt is prepared in isopropanol.

EXAMPLE 3

The following compounds are prepared essentially according to theprocedures set forth above in Examples 1 and 2:

(a) 1-(quinazolin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazine oxalate(m.p. 207-209° C.)

(b) 1-(quinoxalin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazine oxalate(m.p. 209-212° C.)

(c) 1-(3-methylquinoxalin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazinehydrobromide (m.p. 293-295° C.)

(d) 1-(quinolin-2-yl)-4-(1-[4-methylphenyl]-methyl)piperazinehydrochloride (m.p. 278-280° C.)

(e) 1-(quinolin-2-yl)-4-(1-[4-ethylphenyl]methyl)piperazine

(f) 1-(quinolin-2-yl)-4-(1-[4-isopropylphenyl]-methyl)piperazinehydrochloride (m.p. 270-271° C.)

(g) 1-(quinolin-2-yl)-4-(1-[4-tert-butylphenyl]-methyl)piperazinehydrochloride (m.p. 285-287° C.)

(h) 1-(quinolin-2-yl)-4-(1-[4-fluorophenyl]-methyl)piperazine

(i) 1-(quinolin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazinehydrobromide (m.p. 268-271° C.)

(j) 1-(quinolin-2-yl)-4-(1-[3,4-dichlorophenyl]-methyl)piperazinehydrobromide (m.p. 285-287° C.)

(k) 1-(quinolin-2-yl)-4-(1-[4-trifluoromethylphenyl]-methyl)piperazinehydrobromide (m.p. 271-273° C.)

(l) 1-(quinolin-2-yl)-4-(1-[4-trifluoromethoxyphenyl]-methyl)piperazine(m.p. 109-110° C.)

(m) 1-(quinolin-2-yl)-4-(1-[3,4-methylenedioxyphenyl]-methyl)piperazinehydrobromide (m.p. 279-280° C.)

(n) 1-(4-methylquinolin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazinehydrobromide (m.p. 215-217° C.)

(o)1-(4,6-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazinehydrobromide

(p)1-(4,7-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazinehydrobromide (m.p. 295-296° C.)

(q)1-(4,8-dimethylquinolin-2-yl)-4-(1-[4-chlorophenyl]-methyl)piperazinehydrobromide (m.p. 262-264° C.)

(r) 1-(quinolin-2-yl)-4-(1-[4-chlorophenyl]ethyl)piperazine hydrobromide(m.p. 285-287° C.)

(s) 1-(4-fluoroquinolin-2-yl)-4-(phenylmethyl)piperazine oxalate (m.p.186-187° C.)

(t) 1-(4-fluoroquinolin-2-yl)-4-(1-[4-fluorophenyl]-methyl)piperazineoxalate (m.p. 191-193° C.)

EXAMPLE 4

1. 2, 4-Dichloro-5,6,7,8-tetrahydroquinazoline

Dihydroxyquinazoline (10 g) is dissolved in phosphorus oxychloride (100mL) and diethyl aniline (15 g). The resulting dark solutuion is broughtto reflux for 24 h, cooled and concentrated. The residue is taken up inchloroform, washed with ice cold 1N NaOH solution, dried andconcentrated. The resulting solid is recrystallized from ethyl acetateto provide the dichloro compound (9.2 g, 76%.

2. 2-Chloro-5,6,7,8-tetrahydroquinazoline

2, 4-Dichloro-5,6,7,8-tetrahydroquinazoline (4 g) is dissolved in 50 mLof methylene chloride and the resulting solution covered with 9% NH₄OHin saturated brine. Zinc (4 g) is added and the resulting mixture gentlyrefluxed overnight. After filtration through celite, the organic layeris washed with water, dried and concentrated.

3.1-(5,6,7,8-tetrahydroquinazolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazineoxalate

A solution of 1 g of 2-hydroxy-5,6,7,8-tetrahydroquinazoline and 0.1 gof diethylaniline in 10 mL of phosphorus oxychloride is refluxed for 2h, and subsequently cooled and concentrated. The residue is taken up inchloroform and washed with excess 3 N NaOH solution. The organic layeris dried and concentrated to provide2-chloro-5,6,7,8-tetrahydroquinazoline (1.1 g) as an orange solid.

A portion of this material (200 mg, 1.2 mmol) is mixed neat with anequivalent amount of 1-(4-chlorobenzyl)piperazine (250 mg) and theresultant mixture is heated to 150° C. under nitrogen for 30 min. Uponcooling, the resulting homogenous mixture is partitoned betweenchloroform and 10% NH₄OH solution. The organic layer is dried andconcentrated. The residue is then taken up in hot isopropanol (3 mL) andtreated with oxalic acid (108 mg) in a minimum amount of hot isopropanolto provide the desired product, which may also be named as2-((4-(4-chlorophenyl)-piperazinyl)methyl)-5,6,7,8-tetrahydroquinazoline,oxalic acid salt, as an off-white solid (213 mg, 41%, m.p. 210-212° C.).

EXAMPLE 4

1-(5,6,7,8-tetrahydroquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrobromide

A solution of 0.7 g of 2-hydroxy-5,6,7,8-tetrahydroquinoline (preparedaccording to the methods outlined by Meyers et al., J. Org. Chem., 29:1435-1438, 1964) and 0.1 g of diethylaniline in 7 mL of phosphorusoxychloride is refluxed for 2 h, cooled and concentrated. The residuetaken is up in chloroform, washed with excess 3 N NaOH solution and theorganic layer dried and concentrated to provide crude2-chloro-5,6,7,8-tetrahydro-quinoline (0.45 g) as an oil.

A portion of this material (150 mg, 0.9 mmol) is mixed neat with anequivalent amount of 1-(4-chlorobenzyl)piperazine (189 mg) and theresultant mixture heated to 150° C. under nitrogen for 20 min. Uponcooling, the resulting homogenous mixture is triturated with isopropanolto provide the desired product, which may alternatively be named as4-(4-chlorophenyl)-1-(2-5,6,7,8-tetrahydroquinolylmethyl)piperazine,hydrobromide salt, as an off-white solid (274 mg, 81%, m.p. 281-283°C.). ¹H NMR (CDCl₃) 7.31 (s, 4H), 7.18 (d, J=4 Hz, 1H), 6.42 (d, J=4 Hz,1H), 3.56 (s, 2H), 3.52 (m, 4H), 2.75 (m, 2H), 2.6 (m, 6H), 1.7-1.85 (m,4H).

The following compound is prepared essentially according to theprocedures set forth above in Examples 3 and 4:

(a)1-(6-methoxy-4-methylquinolin-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazinehydrochloride (m.p. 250-253° C.)

EXAMPLE 5

1-(Naphth-2-yl)piperazine

A mixture of phosphorus pentoxide (17 g) and triethyl aminehydrochloride (16.5 g) is heated and stirred under nitrogen until melted(240° C.). To this mixture is then added 2-aminonaphthalene (5.72 g) anddiethanolamine (4.2 g), and the temperature maintained for 0.5 h. Aftercooling to approx. 100° C., the mixture is poured onto ice, neutralizedwith 1N NaOH, and extracted with chloroform. The organic layer is washedwith water, dried and concentrated. The hydrochloride salt is preparedin ethanol (8.1 g, m.p. 265-266° C.)

2. 1-(Naphth-2-yl)-4-(1-[4-methylphenyl]methyl-piperazine Hydrochloride

A solution of l-(naphth-2-yl)piperazine (212 mg, 1 mmol) and4-methylbenzyl bromide (185 mg, 1 mmol) in acetonitrile (10 mL) overpotassium carbonate (500 mg) is stirred for 48 h. After partitioningbetween ether and water, the organic layer is extracted with 1N HClsolution, and the acidic layer is then neutralized with 6 N sodiumhydroxide and extracted with chloroform. The combined chloroformextracts are dried over sodium sulfate and concentrated. The resultingoil is taken up in isopropanol and treated with a saturated solution ofHCl (g) in ethyl acetate to provide the product as a white crystallinesolid (374 mg, 86%).

EXAMPLE 6

The following compounds are prepared essentially according to theprocedures set forth above in Example 5:

(a) 1-(naphth-2-yl)-4-(1-[4-chlorophenyl]methyl)piperazine hydrochloride(m.p. 216-218° C.)

(b) 1-(naphth-2-yl)-4-(1-[4-methylphenyl]methyl)piperazine hydrobromide(m.p. 222-223° C.)

(c) 1-(naphth-2-yl)-4-(1-[4-fluorophenyl]methyl)piperazine hydrobromide(m.p. 244-246° C.)

(d) 1-(naphth-2-yl)-4-(1-[3-fluorophenyl]methyl)piperazine hydrobromide(m.p. 253-255° C.)

(e) 1-(naphth-2-yl)-4-(1-[2-fluorophenyl]methyl)piperazine hydrobromide(m.p. 239-240° C.)

EXAMPLE 7 Assay for D₂ and D₄ Receptor Binding Activity

The pharmaceutical utility of compounds of this invention is indicatedby the assays for dopamine receptor subtype affinity described below.

Pellets of COS cells containing recombinantly produced D₂ or D₄receptors from African Green monkey are used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and pH 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenized. The sample is again centrifuged as described aboveand the final tissue sample is frozen until use. The tissue isresuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mMNaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³H-YM 09151-2 (Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide)andthe compound of interest in a total incubation of 1.0 ml. Nonspecificbinding is defined as that binding found in the presence of 1 mMspiperone; without further additions, nonspecific binding is less than20% of total binding. Binding characteristics for examples of compoundsencompassed within Formula I for the D₂ and D₄ receptor subtypes areshown in Table 2 for rat striatal homogenates.

TABLE 2 Binding of compounds of the invention to D4 and D2 receptorscloned from African Green monkey. Compound Number D₄ K_(i) (nM) D₂ K_(i)(nM) 2 8 >4000 3 11 >4000 6 9 >4000 7 7 1927

Compound numbers in Table 2 relate to compounds shown in Table 1.

The binding characteristics of compounds of Formula I for the D₄receptor, expressed in nM, generally range from about 0.5 nanomolar (nM)to about 25 nanomolar (nM). These compounds typically have bindingconstants for the D₂ receptor of from about 200 nM to more than 1000 nM.Thus, the compounds of the invention are generally at least about 10time more selective for the D₄ receptor than the D₂ receptor.Preferably, these compounds are at least 20, and more preferably atleast 25-50, times more selective for the D₄ receptor than the D₂receptor. Most preferably, these compounds are at least 100 times moreselective for the D₄ receptor than the D₂ receptor.

EXAMPLE 8

A compound described in Arch. Med. Res., 25: 435-440 (Terron et al.,1994), 1-(quinolin-2-yl)-4-benzylpiperazine (Comparative Compound B),was evaluated in the assays described above. Comparative Compound Bdemonstrated relatively weak interaction with the D₄ receptor subtype(IC₅₀=194 nM).

A compound described in Toxicol. Appl. Pharmacol., 7: 257-267 (Schmidtand Martin, 1965), 1-naphth-2-yl-4-benzylpiperazine (ComparativeCompound A), was evaluated in the assays described above. ComparativeCompound A demonstrated relatively weak interaction with the D₄ receptorsubtype (IC₅₀=33 nM).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable addition salt thereof, wherein: R_(c) represents hydrogen, halogen or C₁-C₆ alkyl; R₁ and R₂ independently represent hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₄ alkoxy, trifluoromethyl, trifluoromethoxy or SO₂NH₂, provided that, when R₃ and R₄ are both hydrogen, R₁ and R₂ are not hydrogen simultaneously; and provided that, R₁ and R₂ cannot both be hydrogen simultaneously, and provided that when R₁ is C₁-C₄ alkyl or halogen, R₂ is halogen, hydroxy, C₂-C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂NH₂; or R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group or a C₁-C₃ alkylene oxy group; and provided that when R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group or a C₁-C₃ alkylene oxy group, at least one of R₃ and R₄ is halogen or C₂-C₆ alkyl; R₃ and R₄ are the same or different and represent hydrogen, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkyl amino where each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl; with the proviso that when either R₃ or R₄ is methyl, then the other is halogen, C₂-C₆ alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkyl amino where each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl; and R₆ and R₇ independently represent hydrogen or C₁-C₆ alkyl.
 2. A compound according to claim 1, wherein at least one of R₁ and R₂ is halogen, alkyl, trifluoromethyl, or trifluoromethoxy, provided that, when R₁ is C₁-C₄ alkyl or halogen, R₂ is halogen, C₂-C₆ alkyl, trifluoromethyl, or trifluoromethoxy.
 3. A compound according to claim 1, wherein at least one of R₁ and R₂ is chloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl, trifluoromethyl, or trifluoromethoxy, provided that, when R₁ is C₁-C₄ alkyl or halogen, R₂ is halogen, C₂-C₆ alkyl, trifluoromethyl, or trifluoromethoxy.
 4. A compound according to claim 1, wherein R₃ and R₄ are hydrogen, R₁ is methyl or chloro, and R₆ and/or R₇ is methyl.
 5. A compound of the formula:

or a pharmaceutically acceptable addition salt thereof, wherein: R_(c) is hydrogen, halogen or C₁-C₆ alkyl; R₁ and R₂ independently represent hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C_(l)-C₄ alkoxy, trifluoromethyl, trifluoromethoxy or SO₂NH₂; provided that, R₁ and R₂ cannot both be hydrogen simultaneously, and when R₁ is C₁-C₄ alkyl or halogen, R₂ is halogen, hydroxy, C₂-C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂NH₂; or R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group or a C₁-C₃ alkylene oxy group and provided that when R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group or a C₁-C₃ alkylene oxy group, at least one of R₃ and R₄ is halogen or C₂-C₆ alkyl; and R₃ and R₄ independently represent hydrogen, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkyl amino, cyano or trifluoromethyl.
 6. A compound according to claim 1, wherein at least one of R₃ and R₄ is halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, alkylthio, hydroxy, amino, mono or dialkyl amino where each alkyl is C₁-C₆ alkyl, cyano or trifluoromethyl; R₁ is C₁-C₄ alkyl or halogen; and R₂ is C₁-C₄ alkoxy.
 7. A compound according to claim 1, wherein R_(c) is halogen or C₁-C₆ alkyl; R₁ is C₁-C₄ alkyl or halogen; and R₂ is C₁-C₄ alkoxy.
 8. A compound according to claim 1, wherein the fused bicyclic ring system contains at least one saturated carbon-carbon bond; and R₂ is halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂NH₂.
 9. A compound according to claim 1, wherein the fused bicyclic ring system contains at least two saturated carbon-carbon bonds; and R₂ is halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂NH₂.
 10. A compound according to claim 1, wherein R₁ and R₂ together represent 3,4-methylenedioxy; and at least one of R₃ and R₄ is halogen.
 11. A compound according to claim 1, wherein R₁ and R₂ together represent 3,4-methylenedioxy; and at least one of R₃ and R₄ is C₂-C₆ alkyl.
 12. A compound according to claim 1, wherein the fused bicyclic ring system contains at least one saturated carbon-carbon bond; R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group; and at least one of R₃ and R₄ is halogen.
 13. A compound according to claim 1, wherein the fused bicyclic ring system contains at least two saturated carbon-carbon bonds; R₁ and R₂ together represent a C₁-C₂ alkylene dioxy group; and at least one of R₃ and R₄ is halogen. 